This application addresses NIMH broad Challenge Area (04) "Clinical Research" and specific challenge topic 04-MH-102: "refining categories of clinical phenotypes for mental health research purposes". We propose an innovative study aimed at refining and validating a clinical phenotype for "paternal age related schizophrenia" (PARS). Paternal age may account for >25% of all cases of schizophrenia and a higher portion of cases in active treatment. This work is aimed at the heterogeneity of schizophrenia, which limits efforts to optimize treatment and to achieve prevention and cure. This heterogeneity is rarely met directly. Genetic studies employ huge sample sizes and clinical researchers target cognitive or negative symptom domains, which are found across the disorder and are associated with adverse outcomes. However, the neural origins and optimum treatment of these domains may differ crucially between schizophrenia subgroups. Potentially progressive and/or remediable substrates remain obscured by heterogeneity. In post hoc analyses (from our earlier-funded NIMH CMHC in Schizophrenia) we found that sporadic cases with paternal age >35 years (a proxy for PARS) had distinct patterns of symptoms, cognition, course and sex-differences versus other (NonPARS) cases. The subgroups also differed in neural circuitry;PARS had lower metabolism in cingulate/paracingulate cortices and the inferior frontal region than controls or the other cases. Congruently, decreasing prefrontal N-Acetyl Acetate on magnetic resonance spectroscopy (MRS) was associated with advancing paternal age in sporadic cases. We propose to prospectively characterize 40 PARS and 40 NonPARS schizophrenia cases and 20 healthy controls. We will assess clinical measures, quality of life, moderating exposures, and other risk factors and obtain neuroimaging data with a 3T (and up to a 7T) MRI/MRS. We will compare features of the anterior cingulate and hippocampus across the groups, controlling for individual BDNF (val66met) haplotype, which is associated with schizophrenia and influences neuroanatomy. We will identify the specific dimensions of cognition and behavior in PARS that map on to particular brain circuitry. Sophisticated data analytic techniques will be used to validate the clinical phenotype of PARS. Genetic samples will also be used in the future to validate the genetic substrates of PARS that we identify in 3R01MH059114 (Jerusalem Perinatal Cohort Schizophrenia Study) or which are nominated by other research efforts. This study is ready to be launched immediately at a large public hospital that serves a diverse and underserved population. The etiology and neurobiological underpinnings of schizophrenia may plausibly differ between latent discrete subgroups of cases. By refining and validating a clinical phenotype for PARS, we will create novel opportunities for tailored treatment interventions in a large portion of cases and we will also have a key phenotype for genetic research. Schizophrenia is a devastating chronic illness with an onset in young adulthood, typically causing deterioration and life long disability. Treatment approaches for schizophrenia are limited due to the heterogeneity of this disease. This project will categorize Paternal Age Related Schizophrenia (PARS) and probe the neurobiological and genetic underpinnings of this phenotype.